Systematic lupus erythematosus (SLE)is an intense inflammatory autoimmune disease that affects up to 2.0 million people in the USA. SLE is predominantly a disease of women and is particularly virulent in children and minority populations. Neuropsychiatric SLE (NPSLE), which can occur in over 50 percent of SLE patients, causes considerable morbidity and increased health care costs. Major NPSLE is characterized by seizures, psychosis, movement disorder, cerebral infarction, cognitive dysfunction, or death. There is no etiology-based standard for diagnosing NPSLE, thus, diagnosis depends of clinical judgement. Research and therapy of NPSLE is hampered by the absence of a reliable, objective technique to diagnose and classify NPSLE. We demonstrate that magnetic resonance (MR) measures of the neuronal marker N-acetylaspartic acid (NAA), spin-spin relaxation (T2), and anatomic lesions in the brain are sensitive to NPSLE and reveal injury difficult to detect by other methods, including histopathology at autopsy. These techniques segregate NPSLE patients into clinically relevant subgroups. Further preliminary data links NAA decreases to neurocognitive dysfunction, increased disability, and risk of death. This proposal consists of a 3 year study to determine the relationship between MR-based quantitative neurometabolic measures of brain injury and neurocognitive decline in a well defined NPSLE cohort. The first phase will determine the relationship between chronic injury and neurocognitive status. 120 patients with NPSLE in the inactive phase will be studied using MR to determine neurometabolites, quantitative T2, lesion and volume changes, and neurocognitive testing to determine brain function. Normal controls will provide normative data. The second phase of the proposal focuses on the relationship between measures of brain injury and neurocognitive decline in periods of acute NPSLE disease activity. Patients with newly active NPSLE will be matched with patients with similar levels of SLE activity and immunosuppressive therapy, but without NPSLE. These patients will be studied repeatedly over a 24 week period following an acute episode. We expect that our results will confirm our preliminary findings of a link between brain injury and brain function in NPSLE. This study will provide the basis for quantitative MRS and MRI as diagnostic technique in NPSLE. This project is anticipated to have considerable impact on both the management and future research of NPSLE.